Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.

BCAA transamination is essential in clear cell renal cell carcinoma for glutamate-derived glutathione production and cell viability under glutamine limitation, enabling resistance to CB-839.

• Why it matters: ccRCC shows selected traits suggesting altered BCAA transamination and oxidation, yet glutaminase inhibition has been ineffective clinically, leaving the metabolic basis unclear.
• What they did: The study genetically modulated BCAA oxidation and found little effect on ccRCC growth in vitro and in vivo, while targeting BCAA transamination reduced glutathione biosynthesis and redox homeostasis during glutaminase inhibition with CB-839.
• The result: In vitro and in vivo, inhibiting BCAA transamination sensitized ccRCC to CB-839 by decreasing glutathione and redox homeostasis, revealing a vulnerability that may explain prior CB-839 trial failures.